The present invention relates to new processes for making the torsemide intermediate, (3-sulfonamide-4-chloro)pyridine. The present invention relates to new processes for making torsemide.
1-Isopropyl-3-[(4-m-toluidino-3-pyridyl) sulfonyl] urea, which has the chemical structure 
is approved, under the trademark DEMADEX(copyright), by the U.S. Food and Drug Administration for the treatment of hypertension and edema associated with congestive heart failure, renal disease, or hepatic disease. The USAN approved generic name for this compound is torsemide, although this compound is also referred to as xe2x80x9ctorasemidexe2x80x9d in the art. Torsemide is a loop diuretic that has been found to be particularly effective for the treatment of edema associated with chronic renal failure.
The synthesis of torsemide, torsemide intermediates and torsemide derivatives are described in the following references: Delarge, Ann. Pharm. Fr. 31, 467-474 (1973); Delarge, Mem. Acad. R. Med. Belg. 47(3), 131-210 (1974); E. Koenigs et al, Chem. Ber. 57, 2080-2082 (1924); L. Thunus, Ann. Pharm. Fr. 33, 487 -494 (1975); Kondo, et al. Iyakuhin Kenkyu, 25(9), 734-50 (1994); EP 618,209; and U.S. Pat. Nos. 2,516,025; 6,674,794; 4,244,950 and Re. 30,633; all of which are incorporated herein by reference. U.S. Pat. No. 4,244,950 and Re. 30,633, all of which are incorporated herein by reference.
A process for the preparation of the torsemide intermediates (3-sulfonamide-4-chloro)pyridine, 3-sulfomamide-4-(3xe2x80x2-methylphenyl) aminopyridine and torsemide is described in Scheme I. 
In known processes where (3-sulfonamide-4-chloro)pyridine is made from (3-sulfonylchloride-4-chloro)pyridine (SCCPYxe2x86x92SAMPCY), the reaction is performed in a polar solvent, such as, acetone or dioxane, or in melted reagent as a solvent in the presence of large excess of ammonium hydroxide. By these known processes, (3-sulfonamide-4-chloro)pyridine (SCCPY), is added dropwise into an aqueous solution of ammonium hydroxide. The dropwise addition of (3-sulfonamide-4-chloro)pyridine into an excess of ammonium hydroxide is a method to try to minimize the condensation of (3-sulfonamide-4-chloro)pyridine with the newly formed desired product, (3-sulfonamide-4-chloro)pyridine (SAMPCY). These harsh reaction conditions necessitate a great effort in purifying the resulting product as well as creating environmental waste disposal issues associated with neutralizing and disposing of large volumes of concentrated basic solutions. The highly basic conditions make the procedures employing a large excess of base very costly. Thus in such conditions the desired (3-sulfonamide-4-chloro)pyridine is made in low yields, of about 50%, and is isolated with a high percentage of impurities thus requiring additional purification steps. It is desirable to have a process for making (3-sulfonamide-4-chloro)pyridine without the condensation of (3-sulfonamide-4-chloro)pyridine and (3-sulfonamide-4-chloro)pyridine. It is also desirable to have a process for making (3-sulfonamide-4-chloro)pyridine which gives high yields and high purity which is suitable for large scale manufacturing procedures.
In known processes where torsemide is made from 3-sulfonamide-4-3xe2x80x2-methylphenyl) aminopyridine, the reaction may be performed in dioxane or dichloromethane in the presence of triethyl amine and isopropyl-isocyanate. Under such conditions the desired torsemide is made in low yields and is isolated with a high percentage of impurities thus requiring additional purification steps. The yields of these processes are low, highly variable and not are not suitable for large scale manufacturing processes. It is therefore desirable to have processes for making torsemide which gives high yields and high purity which uses solvents that are suitable for large scale manufacturing procedures.
The present invention relates to s process for making a compound of the formula: 
comprising the steps of: (a) adding a compound of the formula 
to an organic solvent; (b) adding ammonium hydroxide in an amount of about 1.75 to about 2.25 mole equivalents; and (c) isolating the compound of the formula: 
wherein X1 and X2 are each independently chloro, fluoro or bromo.
In a preferred embodiment of the present invention, X1 and X2 are both chloro.
In another preferred embodiment of the present invention, the organic solvent is selected from the group consisting of t-butyl-methyl ether, toluene, acetonitrile, methyl-isobutyl ketone, ethyl-methyl ketone, acetone, benzene, xylene, ethanol and isopropanol.
In another embodiment of the present intention, the organic solvent is t-butyl-methyl ether.
In another embodiment of the present intention, the ammonia is an aqueous solution.
In another embodiment of the present intention, the ammonia is added to the solution of step (a).
In another embodiment of the present invention, the ammonia is added in an amount of about 1.75 to about 2.25 mole equivalents
The present invention also relates to a process for making (3-sulfonamide-4-chloro)-pyridine comprising the steps of: (a) adding (3-sulfonylchloride-4-chloro)pyridine to an organic solvent; (b) adding ammonia; and isolating (3-sulfonamide-4-chloro)pyridine.
In a preferred embodiment of the present invention, the organic solvent is selected from the group consisting of t-butyl-methyl ether, toluene, acetonitrile, methyl isobutyl ketone, ethyl methyl ketone, acetone, benzene, xylene, ethanol and isopropanol. In another embodiment of the present intention, the organic solvent is t-butyl methyl ether. In another embodiment of the present intention, the ammonia is added as an aqueous solution. In another embodiment of the present intention, the ammonia is added to the solution of step (a). In another embodiment of the present invention, the ammonia is added in an amount of about 1.75 to about 2.25 mole equivalents
The present invention also relates to a process for preparing torsemide comprising the step of reacting 3-sulfonylamide-4(3xe2x80x2-methylphenyl)aminopyridine with isopropyl isocyanate in the presence of triethyl amine in a solvent selected from the group consisting of acetonitrile, toluene, acetone, ethyl acetate and butyl acetate, and mixtures thereof. In a preferred embodiment of the present invention, the solvent is acetone. In another preferred embodiment of the present invention, the solvent is acetonitrile.
The present invention relates to new processes for making the torsemide intermediate (3-sulfonamide-4-chloro)pyridine. The methods of the present invention provide for the synthesis of (3-sulfonamide-4-chloro)pyridine in substantially higher yields and higher purity than previously reported. The intermediate (3-sulfonylchloride-4-chloro)pyridine may be prepared from 4-hydroxy-3-pyridine sulfonic acid by methods known in the art, including methods disclosed in Canadian Patent No.: 1,051,888, and J. Med. Chem., 36, 3211-3213, 1993, the content of both are incorporated herein by reference.
By the methods of the present invention, a compound of formula IIxe2x80x2, wherein X1 and X2 are each independently chloro, fluoro or bromo; is added to a suitable organic solvent (Scheme II). Preferably, X1 and X2 are chloro. Suitable organic solvents include acetonitrile, ethers, such as, t-butyl methyl ether (MTBE), alcohols, such as, ethanol and isopropanol, ketones, such as, methyl-isobutyl ketone (MIBK), ethyl methyl ketone and acetone; and substituted or unsubstituted aromatics, such as, benzene and xylene. A preferred solvent is t-butyl methyl ether. Ammonia is then added to the mixture which may cause the mixture to rise in temperature. Preferably, about 2 mole equivalents of ammonia are added. Ammonia may be added in the form of gaseous ammonia or ammonium hydroxide, and more preferably as an aqueous solution of ammonium hydroxide. Preferably ammonium hydroxide is added as a 25% aqueous solution. The solution is cooled to room temperature and stirred until the reaction is substantially complete, e.g., 1 to 1.5 hours, preferably one hour. Completion of the reaction may be monitored by pH; which is indicated when the pH stops decreasing and stabilizes. The pH of the solution is adjusted to about 8xc2x10.1 by the addition of ammonium hydroxide to induce the precipitation of crystals of the compound of formula IIIxe2x80x2. The compound of the formula IIIxe2x80x2 wherein X1 is chloro, fluoro or bromo; is isolated upon filtering the solution followed by drying (Scheme II). Preferably X1 is chloro. 
In an embodiment of the present invention, a compound of the formula II, (3-sulfonylchloride-4-chloro)pyridine, is added to an organic solvent. Suitable organic solvents include acetonitrile, ethers, such as, t-butyl methyl ether (MTBE), alcohols, such as, ethanol and isopropanol, ketones, such as, methyl-isobutyl ketone (MIBK), ethyl methyl ketone and acetone; and substituted or unsubstituted aromatics, such as, benzene and xylene. A preferred solvent is t-butyl methyl ether. Approximately 1.75 to about 2.25 mole equivalents of ammonia is then added to the solution. Preferably, about 2.15 mole equivalents of ammonia are added. Ammonia may be added in the form of gaseous ammonia or ammonium hydroxide, and more preferably as an aqueous solution of ammonium hydroxide. Preferably ammonium hydroxide is added as a 25% aqueous solution. Addition of the ammonia may cause the temperature of the solution to rise. The solution is cooled to room temperature and stirred until the reaction is substantially complete, e.g., 1 to 1.5 hours, preferably one hour. Completion of the reaction may be monitored by pH; which is indicated when the pH stops decreasing and stabilizes. The pH of the solution is adjusted to about 8xc2x11 by the addition of ammonium hydroxide to induce the precipitation of crystals of (3-sulfonamide-4-chloro)pyridine, the compound of the formula III. (3-Sulfonamide-4-chloro)pyridine, the compound of the formula III, is isolated upon filtering the solution followed by drying. The (3-sulfonamide-4-chloro)pyridine is isolated in a high yield of about 74%. By the present methods, the (3-sulfonamide-4-chloro)pyridine is isolated in an unexpectedly high purity of about 93% to about 97%.
Thus, surprisingly the present methods provide processes for making high purity (3-sulfonamide-4-chloro)pyridine while using a high concentration of the starting material, (3-sulfonylchloride-4-chloro)pyridine. In contrast to the known methods, the present methods surprisingly yield (3-sulfonamide-4-chloro)pyridine substantially free of by-products resulting from the condensation of the starting material and product, (3-sulfonylchloride-4-chloro)pyridine and (3-sulfonamide-4-chloro)pyridine, which is observed in the known processes. 
The present method thus provides a new process with high yields and high purity which is suitable for use in large scale reactions. The high purity also reduces the need for additional purification steps.
The present invention also relates to a new process for making torsemide from 3-sulfonamide-4-(3xe2x80x2-methylphenyl) aminopyridine. 3-Sulfomamide-4-(3xe2x80x2-methylphenyl) aminopyridine may be prepared from (3-sulfonamide-4-chloro)pyridine by methods known in the art, including methods disclosed in U.S. Pat. No.: 3,904,636, the content of which is incorporated herein by reference.
By the processes of the present invention, a compound of the formula IV, 3-sulfomamide-4-(3xe2x80x2-methylphenyl) aminopyridine, is added to triethylamine (TEA) and an organic solvent (Scheme IV). Suitable solvents are acetonitrile, toluene, acetone, ethyl acetate and butyl acetate, and mixtures thereof Preferred solvents are acetonitrile and acetone. A more preferred solvent is acetonitrile. Isopropyl isocyanate (IPIC) is then added dropwise to the solution and the solution is heated to about 40xc2x0 C. The resulting mixture is then stirred at about 38xc2x0 C. to about 42xc2x0 C. until there is complete dissolution of all the reactants, about 45 to 90 minutes. The mixture is then cooled to room temperature and stirred for a suitable time, about 1.5 to about 2.5 hours and preferably about 2 hours. The pH of the mixture is then adjusted to about 4.3xc2x10.3, preferably to 4.3 with increasing the temperature to about 35xc2x0 C. The pH may be lowered with hydrochloric acid. The mixture is cooled room temperature, followed by filtration and washing. The wet crude product is triturated, followed by drying to yield crude torsemide. The yield of isolated crude torsemide is about 81.5%. The purity of the isolated crude torsemide is about 98% to about 99.9% which is a substantial improvement over the methods known in the art. 